Project 1 - Ascending thoracic aortic aneurysms progressively enlarge over time, typically leading to an acute type A dissection in the absence of prophylactic surgical repair. Therefore, thoracic aortic aneurysms and type A dissections are associated conditions and are termed TAAD for this proposal. We determined that TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 15% of TAAD patients. We mapped the first three loci for the condition and have determined that the defective gene at the TAAD2 locus is transforming growth factor beta receptor type II (TGFBR2). Identification of TGFBR2 as the defective gene at the TAAD2 locus has provided insight into the role of TGF-beta signaling as a mechanism leading to aneurysm formation. Our preliminary data demonstrates the surprising finding that although the TGFBR2 R460 mutations disrupt TGF-beta signaling when expressed in cells lacking the wild type receptor, aortic smooth muscle cells (SMCs) explanted from patients heterozygous for the mutation demonstrate paradoxical upregulation of TGF-beta signaling in the absence of stimulation with TGF-beta ligand. Furthermore, the majority of aortic SMCs explanted from unrelated patients with familial TAAD who do not have TGFBR2 mutations (5 out of 6 cell strains) demonstrate the same paradoxical upregulation of TGF-beta signaling in the absence of ligand. Based on our genetic studies and preliminary data, we hypothesize that dysregulation of TGF-beta signaling in aortic SMCs is common in familial thoracic aortic aneurysms and dissections. The first aim is to determine the mechanism leading to stimulation of the TGF-beta pathway in the absence of ligand in aortic SMCs heterozygous for the TGFBR2 mutation. We will then proceed to characterize the phenotype of these aortic SMCs. In addition, we will determine the frequency of dysregulation of TGF-beta signaling in aortic SMCs explanted from familial and sporadic TAAD patients and investigate the etiology of this dysregulation. Finally, we will characterize the clinical phenotype associated with TGFBR2 mutations using four mutigenerational families. The long-term goal of these studies is to identify the genes that predispose individuals to familial TAAD and determine the phenotype associated with these mutations so that proper clinical management can be provided to prevent premature deaths in these families. In addition, we hope to develop rational therapy to treat this fatal disease through the characterization of molecular pathways leading to this disease.